Stroke is a cerebrovascular event, which occurs when the normal bloodflow to the brain is disrupted, and the brain receives too much or too little blood. Stroke is one of the leading causes of death worldwide, and is also one of the most common causes of neurologic disability.
Ischemic stroke, which is the most common type of stroke, results from insufficient cerebral circulation of blood caused by obstruction of the inflow of arterial blood. Normally, adequate cerebral blood supply is ensured by a system of arteries within the brain. However, various disorders, including inflammation and atherosclerosis, can cause a thrombus, i.e., a blood clot that forms in a blood vessel. The thrombus may interrupt arterial blood flow, causing brain ischemia and consequent neurologic symptoms. Ischemic stroke may also be caused by the lodging of an embolus (an air bubble) from the heart in an intracranial vessel, causing decreased perfusion pressure or increased blood viscosity with inadequate cerebral blood flow. An embolus may be caused by various disorders, including atrial fibrillation and atherosclerosis.
A second type of stroke, hemorrhagic stroke, involves a hemorrhage or rupture of an artery leading to the brain. Hemorrhagic stroke results in bleeding into brain tissue, including the epidural, subdural, or subarachnoid space of the brain. A hemorrhagic stroke typically results from the rupture of an arteriosclerotic vessel that has been exposed to arterial hypertension or to thrombosis.
During acute ischemic stroke, i.e., the period from the cerebrovascular event up to 24 hours after the event, the arterial occlusion results in an immediate infarcted core of brain tissue, where cerebral blood flow is significantly reduced, for example to less than 20% of the normal blood flow. The infarcted core suffers irreversible damage due to significant cell death. The length of time that ischemia persists, and the severity of the ischemia, contribute to the extent of injury. An area around the infracted core, known as the ischemic penumbra, suffers a delayed and less severe infarct. For example, during acute stroke the penumbra may have a reduction in blood flow of from about 20-40% of normal blood flow.
While not fully understood, the pathogenesis of ischemic stroke involves a complex cascade of multiple interacting biochemical events, which lead to acute neurologic injury and reduced neurological function. Ischemia results in the depletion of cellular energy stores of ATP, and the failure of sodium and potassium ion pumps. This leads to depolarization of neurons in the brain, and consequent excitotoxicity, i.e. excessive activity of excitatory amino acids, including glutamate, resulting in neuronal damage. In addition, the cascade leads to an increase in intracellular calcium. The presence of intracellular calcium in turn leads to the activation of intracellular enzymes and neuronal death. Lyden et al., J Stroke and Cerebrovasc Dis 2000;9 (6, Suppl 2);9-14. Excitotoxicity also results in the activation of enzymes, phospholipases, proteases, and nitric oxide synthases, and the production of oxygen free radicals. Each of these events contribute to the neuronal cell death of stroke. Nicotera et al, J Cerebr Blood Flow & Metab 19(6); 583-591 (1999).
One opportunity for pharmacologic intervention in stroke is the prevention or reduction of risk of stroke in patients at risk for stroke. There are many known risk factors for stroke, including vascular inflammation, atherosclerosis, arterial hypertension, diabetes, hyperlipidemia and atrial fibrillation. At risk patients have been treated with agents to control blood pressure or manage blood lipid level, and have been treated with antiplatelet agents (such as clopidrogel) and anticoagulants. Patients who have suffered myocardial infarction and are at risk for stroke are often treated with angiotensin-converting enzyme inhibitors (ACE inhibitors) or beta adrenergic antagonists (beta blockers).
A second opportunity for pharmacological treatment of stroke is the treatment of acute stroke. However, current pharmacologic therapies for treating acute stroke are limited to restoring blood flow within a narrow therapeutic time window of less than three hours after stroke. The only agents which have shown effectiveness in treating acute stroke are thrombolytics (such as rt-PA) and urokinase. There remains a need for agents which are effective within a longer therapeutic time window.
Another opportunity for pharmacological treatment of stroke is recovery or restoration after the acute stroke period, i.e. the reduction or prevention of secondary cell damage in the penumbra. Although some neuroprotective agents have demonstrated efficacy in preclinical animal models of stroke, favorable results have not always been duplicated in human clinical trials. There remains a need for agents which are effective in reducing or preventing secondary cell damage after stroke.
It would be desirable to obtain a single pharmaceutical agent which can be used in more than one of the above-mentioned opportunities for treating stroke. Such an agent may be administered to patients at risk for stroke, and also may be administered to patients suffering from acute stroke, or patients undergoing treatment for recovery or restoration after the acute stroke period. Such an agent may also target more than one distinct mechanism in the biochemical cascade of stroke.
One class of neuroprotective agents which are known to be useful for treating stroke are reactive astrocyte inhibitors. Astrocytes are a type of cell found in the central nervous system. Astrocytes supply essential substrates and remove toxins from the area of the brain surrounding neurons, and help to maintain suitable levels of antioxidants in the brain. See Wilson et al, Can J Physiol Pharmacol 75:1149-1163 (1997). However, recent evidence indicates that astrocytes may have a broader role in the modulation of neural networks. For example, astrocytes may express voltage gated ion channels and neurotransmitter receptors. Bachoo et al, Proc Nat'l Acad Sci, 101:8384-8389 (2004).
Thus, compounds which may inhibit the production of reactive astrocytes may be useful in the treatment of stroke. A preferred inhibitor of reactive astrocytes is (2R)-2-propyloctanoic acid, shown below:
which is disclosed in U.S. Pat. No. 6,608,221.